Individuals with multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), frequently report symptoms of fatigue that may interfere with performance of daily activities (6,7). MS fatigue may specifically include physiologic fatigue, defined as the failure to maintain an expected work output (8), and more general manifestations such as malaise or lack of energy. The focus of this proposal will be central fatigue, defined as an inability to sustain central drive to spinal motoneurons (9). This type of fatigue commonly coincides with heat exposure, evidenced by reports of decreased motor function and increased symptomatology when MS patients take a warm bath or get into a hot automobile. The observation that heat exposure produces symptom worsening in MS was made over a century ago (11); however, at that time physiologic measures of central conduction were not available. Transcranial magnetic stimulation (TMS) is a technique that has been used to study CNS conduction in normal and diseased populations. TMS studies in individuals with MS have shown variable sensitivity to clinical signs and symptoms (25). This variability may be in part due to the fact that many individuals with MS, especially those with mild disease, demonstrate relatively normal CNS function at rest. However, upon physical exertion or direct heat exposure many MS patients report deterioration of motor function and increased fatigue. The purpose of this AREA proposal is to determine if the fatigue produced by heat exposure in MS patients produces a corresponding change in physiological measures of central conduction and cortical excitability. Measures of cortical and transcallosal conduction will be examined. The specific aims of this proposal are to: 1) compare central motor conduction during normal and thermally stressed conditions by recording motor evoked potential (MEP) amplitudes and latencies in abductor pollicus brevis (APB) muscle, 2) compare the extent of post-exercise depression (FED) of MEPs following fatiguing thumb abduction exercise during normal and thermally stressed conditions, and 3) compare contralateral silent period (SP) and ipsilateral silent period (ISP) latencies and durations during normal and thermally stressed conditions. It is hypothesized that central conduction abnormalities in MS patients will be amplified with increased body temperature. TMS studies performed in the presence of factors that produce fatigue may provide more sensitive physiologic indicators of disease progression and treatment effects. New knowledge about the type and causes of fatigue in MS patients may lead to interventions that can be used to promote maintenance of activities and functional abilities. [unreadable] [unreadable] [unreadable]